According to the National Survey of Drug Use and Health (NSDUH) of 2008, 7.2 million Americans are in need of treatment for Substance-Related Disorders (SRDs), and a large proportion of those need treatment for opiate pain reliever, heroin, and alcohol addiction. Naltrexone (NTX), an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. NTX is also FDA-approved for the treatment of alcohol dependence. Substantial clinical evidence exists for the benefits of NTX treatment in smoking cessation, especially in women. Very intriguing clinical trial data has also been observed in amphetamine-dependent individuals, which is especially important as methamphetamine dependence has no FDA-approved treatment options. Treatment with NTX in the 90's produced variable success rates in addicts; however, current clinical NTX therapy is being optimized based on human pharmacogenetic data. A 30-day depot injection of the drug has been approved for the treatment of opiate addiction and alcoholism; however, postmarketing reports of serious injection site reactions (cellulitis, abscess, and necrosis) have recently required patient warning updates. Transdermal delivery systems offer a number of improvements over other delivery systems. Patches do not require swallowing, eliminating oral side effects; nor do they require skin puncture by syringe needles, eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect, decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers and alcoholics. Transdermal delivery of NTX is desirable for addicts and alcoholics in order to help reduce side effects associated with oral/depot injection therapies and improve compliance. NTX itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs, including NTX. Microneedle products are currently in late-stage clinical trials for vaccine development, but this proposed product would be the first microneedle delivery system for multiple day sustained release systemic treatment. We hypothesize that NTX in combination with microneedle treatment will provide a therapeutic transdermal delivery rate of NTX. The initial screening of the prototype patch will be completed in a Yucatan miniature pig pharmacokinetic study to verify that the patch system developed in vitro performs well in vivo (dose ranging study). The final studies for this proposal will be a group of critical GLP dermatotoxicology studies in animals to assess skin irritation and sensitization potential of the final patches. This final data will be used to apply for an IND, so that a Phase I clinical trial may begin at the end of this project. We will create a marketable and safe drug that will significantly aid in the treatment of addiction.